Clinical Pharmacokinetics of Angiotensin Converting Enzyme (ACE) Inhibitors in Renal Failure

Summary

Arterial hypertension occurs frequently in patients with chronic renal failure. Antihypertensive treatment of arterial hypertension with angiotensin converting enzyme (ACE) inhibitors has been shown to be effective with a low incidence of adverse effects compared with other drug classes. Furthermore, treatment with ACE inhibitors may slow the progression of renal function impairment in certain groups of patients, such as those with diabetes.

Most ACE inhibitors are prodrugs which are converted by hepatic esterolysis to an active diacid metabolite. Only captopril and lisinopril have sufficient oral bioavailability and are given as active drugs. ACE inhibitors can be subdivided into 3 classes with regard to the active group: the majority of ACE inhibitors are carboxyl-containing drugs, a new class of ACE inhibitors possess a phosphoryl-group and captopril and related compounds are sulfhydryl-containing drugs.

The predominant elimination pathway of ACE inhibitors is excretion via the kidneys. Therefore, renal insufficiency is associated with reduced elimination of most ACE inhibitors and, thus, altered pharmacokinetic properties. This is most evident in chronic renal failure when glomerular filtration rates (GFR) are <30 to 40 ml/min (1.8 to 2.4 L/h). As renal clearance decreases, the peak plasma concentration and area under the plasma concentration-time curve of the active drugs or diacids are increased and time to peak concentrations and half-life are prolonged. However, there are large between-drug differences in the changes in pharmacokinetic parameters, resulting in different degrees of drug accumulation after consecutive administration. This leads, for example, to high accumulation rates for drugs such as lisinopril, or cilazaprilat. In contrast, fosinopril, which is also excreted to a large extent by the hepatobiliary pathway, does not seem to accumulate in renal failure.

In general, pharmacokinetics and conversion of prodrugs seem to be slightly affected in chronic renal failure; however, these changes do not appear to be clinically relevant. Efficiency of clearance for prodrugs or active drugs and their respective metabolites by haemodialysis or peritoneal dialysis varies considerably. For some ACE inhibitors, such as captopril or enalapril, the high elimination fraction by haemodialysis necessitates a supplemental dose after dialysis. Other ACE inhibitors, such as quinapril or cilazapril, are only poorly eliminated by haemodialysis or peritoneal dialysis.

Dosage recommendations for treatment with ACE inhibitors in chronic renal failure depend on the specific pharmacokinetic properties of the various agents. For most ACE inhibitors, dosage adjustment is recommended in moderate and severe impairment of renal function, with resultant dosages being 25 to 50% of those recommended for patients with normal renal function.